








key: cord-334603-yt2pmxi3
authors: de Sousa, Eric; Ligeiro, Dário; Lérias, Joana R.; Zhang, Chao; Agrati, Chiara; Osman, Mohamed; El-Kafrawy, Sherif A; Azhar, Esam I; Ippolito, Giuseppe; Wang, Fu-Sheng; Zumla, Alimudin; Maeurer, Markus
title: Mortality in COVID-19 disease patients: Correlating Association of Major histocompatibility complex (MHC) with severe acute respiratory syndrome 2 (SARS-CoV-2) variants
date: 2020-07-18
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.07.016
sha: 
doc_id: 334603
cord_uid: yt2pmxi3

Abstract As the 2019 (COVID-19) pandemic caused by the novel coronavirus, SARS-CoV-2 spreads globally, differences in adverse clinical management outcomes have been associated with associated with age >65years, male gender, and co-morbidities such as smoking, diabetes, hypertension, cardiovascular comorbidity and immunosuppression. Ethnicity has been the focus of attention after data from the United Kingdom showed a disproportionate number of deaths among healthcare workers from black, Asian and other ethnic minority backgrounds (1). In addition to ethnicity, socio-economic factors, prior vaccinations and exposure to other coronaviruses, other factors need to be considered to explain geographical and regional variations in susceptibility, severity of clinical expression of COVID-19 disease and outcomes. In the United States there have been disproportionate COVID-19 death rates among African Americans at around 2.6 times higher than that of other groups. Although these data could be due to multiple cultural and socioeconomic factors an underlying genetic susceptibility to SARS-CoV-2 infection may be a factor.

As the 2019 (COVID-19) pandemic caused by the novel coronavirus, SARS-CoV-2 spreads globally, differences in adverse clinical management outcomes have been associated with associated with age >65years, male gender, and co-morbidities such as smoking, diabetes, hypertension, cardiovascular comorbidity and immunosuppression. Ethnicity has been the focus of attention after data from the United Kingdom showed a disproportionate number of deaths among healthcare workers from black, Asian and other ethnic minority backgrounds (1). In addition to ethnicity, socio-economic factors, prior vaccinations and exposure to other coronaviruses, other factors need to be considered to explain geographical and regional variations in susceptibility, severity of clinical expression of COVID-19 disease and outcomes. In the United States there have been disproportionate COVID-19 death rates among African Americans at around 2.6 times higher than that of other groups. Although these data could be due to multiple cultural and socioeconomic factors an underlying genetic susceptibility to SARS-CoV-2 infection may be a factor.

Genetic factors were thought to play a causative role in the pathogenesis of the SARS outbreak in 2003 in a group of Taiwanese patients, where the HLA-B*4601 haplotype was associated with severity of SARS infection (2) . In Hong Kong Chinese patients a strong association was shown J o u r n a l P r e -p r o o f between HLAB* 0703 and HLA-DRB1*0301 alleles and an increased susceptibility to SARS infection (3) . In contrast, L-SIGN homozygote individuals seem to have a significantly lower risk of SARS infection (4) .

Generally, peripheral blood lymphocytes counts of black Americans show lower neutrophil counts and proportionally higher frequency of lymphocytes compared to the rest of the population (5).

HLA-association studies of SARS-CoV-1 with HLA-ligands for SARS-CoV-2 have been compiled (6) .

The biological and clinical relevance of immune responses to SARS-CoV-2 requires further discussion:

1. Autoimmune associations with COVID-19. Some individuals with COVID-19 experienced neurological symptoms, e.g. Guillain Barre Syndrome (7), suggesting an autoimmune background, which has been associated with MHC alleles (8) . The role of MHC variants in increased susceptibility to infections or, vice versa, immune protection is well known for a number of viral diseases, e.g. the role of MHC alleles in HIV-control, or increased risk for chronic hepatitis B (9). dampens autoimmune responses and confers protection from type I Diabetes (10) (11) associated with strong IFN-production. HLA-DQB1*06:02 has been selected for increased resistance to Yersinia pestis in immigrants from Africa to Europe, engagement of CD4+ T-cells to HLA-DQB1*06:02 leads to increased, pro-inflammatory IL-17 production, independent of the MHC class II presented peptides (12) and confers increased risk to the development of anti-myelin directed autoimmune responses (13) . The haplotypes HLA-DR2-DQ6, DR4-DQ8, and DR3-DQ2 accommodate peptides from infectious pathogens to CD4+ T-cells from Europeans who survived the bottleneck of different, life-threatening infections prevalent in Europe (9). These alleles have also shown to be associated with increased risk for autoimmune diseases, for instance to dietary antigens (celiac disease) (14) in part due to their intrinsic capacity to stimulate stronger IL-17 production, that facilitates Central Nervous System (CNS)associated disease manifestations (15) . (33) . We used for this prediction a 33 residue peptide with the mutation site in the middle (VNKITYGACPKYVKQNTLKLATGMRNVPEKQTR) and thebest fitting peptide with 15 residues that was predicted to binds to HLA-DRB1*04:01, is exactly the peptide reported earlier (33) recognized by a Flu epitope specific T-cell clone. In contrast, the variant (T314K) peptide does not bind ( Table 1) . (40), type 1 diabetes (41, 42) , and Lyme disease induced arthritis (43) . DRB1*09:01 is associated with early childhood myasthenia gravis (44) . DRB3*02:02 is linked to Grave's disease (44) , serum IgG antibodies to Chlamydia pneumoniae with essential hypertension (45) and acute necrotizing encephalopathy (46) In conclusion, there appears to be no selective pressure from MHC class I alleles for SARS-CoV-2 variants tested. Most likely there is selective pressure from MHC class II alleles in regard to binding of the ORF8 (L84S) variants assuming that this mutation may be biologically relevant (25, 26) . This data underlines the need to examine SARS-CoV-2 variants and MHC-associations along with clinical outcomes, a detailed longtime observation with a particular focus on CNS-associated symptoms, particularly in individuals with increased risk to develop autoimmune responses. 

Is ethnicity linked to incidence or outcomes of covid-19?

Association of HLA class I with severe acute respiratory syndrome coronavirus infection

Association of human-leukocyteantigen class I (B*0703) and class II (DRB1*0301) genotypes with susceptibility and resistance to the development of severe acute respiratory syndrome

Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection

Black/white differences in leukocyte subpopulations in men

HLA studies in the context of coronavirus outbreaks

Guillain-Barre syndrome associated with SARS-CoV-2 infection: causality or coincidence?

Association between human leukocyte antigen-DR and demylinating Guillain-Barre syndrome

The MHC locus and genetic susceptibility to autoimmune and infectious diseases

Genetics of the HLA region in the prediction of type 1 diabetes

Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy

HLA class II molecules influence susceptibility versus protection in inflammatory diseases by determining the cytokine profile

DQB1*06:02-Associated Pathogenic Anti-Myelin Autoimmunity in Multiple Sclerosis-Like Disease: Potential Function of DQB1*06:02 as a Disease-Predisposing Allele

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Mechanisms regulating regional localization of inflammation during CNS autoimmunity

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Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells

Separation of IL-4 production from Th cell proliferation by an altered T cell receptor ligand

Longitudinal analysis of Mycobacterium tuberculosis 19-kDa antigen-specific T cells in patients with pulmonary tuberculosis: association with disease activity and cross-reactivity to a peptide from HIVenv gp120

Human papillomavirus type 16 E7 peptide-directed CD8+ T cells from patients with cervical cancer are cross-reactive with the coronavirus NS2 protein

Phylogenetic network analysis of SARS-CoV-2 genomes

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HA1.7, influenza hemagglutinin peptide, and major histocompatibility complex class II molecule, HLA-DR4 (DRA*0101 and DRB1*0401): insight into TCR cross-restriction and alloreactivity

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Impact of Host Molecular Genetic Variations and HIV/HPV Co-infection on Cervical Cancer Progression: A Systematic review

DRB1*03/DRB3*0101, and DRB3*0202 are susceptibility genes for Graves' disease in North American Caucasians, whereas DRB1*07 is protective

E6 and E7 Gene Polymorphisms in Human Papillomavirus Types-58 and 33 Identified in Southwest China

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HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection

Identification of LFA-1 as a candidate autoantigen in treatment-resistant Lyme arthritis

A variant of childhood-onset myasthenia gravis: HLA typing and clinical characteristics in Japan

Association of HLA-DRB3*0202 and serum IgG antibodies to Chlamydia pneumoniae with essential hypertension in a highly homogeneous population from Majorca

Molecular analysis of HLA class IIassociated susceptibility to neuroinflammatory diseases in Korean children

HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy

DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis

Professor Ippolito, Sir Zumla and Prof Mohamed Osman are co-investigators investigators of the Pan-African Network on Emerging and Re-emerging Infections (PANDORA-ID-NET) funded by the European and Developing Countries Clinical Trials Partnership the EU Horizon 2020 Framework Programme for Research and Innovation. Sir Zumla is in receipt of as UK-NIHR senior investigatorship. Professor Maeurer is a member of the innate immunity advisory group of the Gates Foundation and his work is funded by the Champalimaud Foundation. All authors are members of the Global Cancer and Infectious Diseases consortium for Host-directed therapies: Weblink: https://fchampalimaud.org/covid19/aci

